4beta-alkoxy-4alpha-(3&#39;-hydroxyphenyl)-3alpha,5alpha-propanopiperidine derivatives

ABSTRACT

4B-ALKOXY-4A-(3&#39;&#39; - HYDROXYPHENYL) - 3A,5A - PROPHANOPIPERIDINE DERIVATIVES HAVING THE FORMULA   3-R1,9-(R-O-),9-(3-(R2-O-)PHENYL)-3-AZABICYCLO(3.3.1)-   NONANE   WHEREIN R REPRESENTS AN ALKYL GROUP HAVING 1-5 CARBON ATOMS, R1 REPRESENTS AN ALKYL GROUP HAVING 1-5 CARBON ATOMS OR A PHENYLALKYL GROUP HAVING 1-5 CARBON ATOMS IN THE ALKYL MOIETY AND R2 REPRESENTS HYDROGEN ATOM OR AN ALKYLGROUP HAVING 1-5 CARBON ATOMS. THE PIPERIDINE DERIVATIVES ARE USEFUL AS ANALGESICS AND ANTITUSSIVES AND PREPARED BY REACTING 4B (OR A)-HYDROXY-4A ( OR B)-(3-&#39;&#39; HYDROXYPHENYL) - 3A,5A- PROPANOPIPERIDINE DERIVATIVE HAVING THE FORMULA   3-R1,9-(3-(R2&#39;&#39;-O-)PHENYL)-3-AZABICYCLO(3.3.1)NONAN-9-OL   WHEREIN R1 IS THE SAME AS ABOVE AND R2&#39;&#39; REPRESENTS R2 OR AN ALKOXYALKYL GROUP HAVING 1-5 CARBON ATOMS IN EACH ALKYL MOIETY WITH AN ALKANOL HAVING THE FORMULA   R-OH   WHEREIN R IS THE SAME AS ABOVE IN THE PRESENCE OF AN ACID.

United States Patent Office 3 ,812,134 Patented May 21, 1974 3,812,134 4p-ALKOXY-4u-(3-HYDROXYPHENYL)-3a,5a- PROPANOPIPERIDINE DERIVATIVES Issei Iwai, Eiji Ohki, Sadao Oida, Hiromu Takagi, and Yoshihiko Ohashi, Tokyo, Japan, assignors to Sankyo Company Limited, Tokyo, Japan No Drawing. Filed Nov. 8, 1972, Ser. No. 304,810 Claims priority, appligation Japan, Nov. 18, 1971,

Int. Cl. coid 39/00 US. Cl. 260293.54 Claims ABSTRACT OF THE DISCLOSURE 4fi-alkoxy-4u-(3' hydroxyphenyl) 30:,50; propanopiperidine derivatives having the formula C on,-o on.

CHz- H CH3 Rr-N H7 K r CHiC CH:

CH; H CH2 wherein R is the same as above and R represents R or an alkoxyalkyl group having 1-5 carbon atoms in each alkyl moiety with an alkanol having the formula R--OH wherein R is the same as abovein the presence of an acid.

This invention relates to novel 4fl-alkoxy-4a-(3' hydroxyphenyl)-3 a,5a-propanopiperidine derivatives and a process for the preparation thereof.

In particular, this invention relates to 4B-alkoxy-4a-(3'- hydroxyphenyl)-3a,5a-propanopiperidine derivatives having the formula 0 cut-- of on,

cn, H CH1 R1N H, (I)

wherein R represents a straight or branched alkyl group having 1-5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl, R represents a straight or branched alkyl group having l-5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl or a phenylalkyl group having 1-5 carbon atoms in the alkyl moiety such as benzyl and phenylethyl and R represents hydrogen atom or a straight or branched alkyl group having 1-5 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl and pharmaceutically acceptable acid addition salts thereof and also to a process for the preparation of the piperidine derivatives.

We have already reported in Chem. Pharm. Bull. (Japan) 8, 2050-2057 (1970) about a process for the preparation of certain substituted 311,511 propanopiperidines and their analgesic activity.

Now, as a result of various investigations to 3a,5a-p10- panopiperidines, we have unexpectedly found that the novel 4 3-alkoxy-4a-(3' hydroxyphenyl) 30;,50: propanopiperidine derivatives having the formula (I) possess a prominent analgesic and antitussive activities to animals as compared with the known 3a,5u-propanopiperidines.

It is, accordingly, a principal object of this invention to provide novel 3u,5a-propanopiperidine derivatives of the above formula (I) and acid addition salts thereof which are useful as potent analgesics and antitussives.

Another object of this invention is to provide a process for the preparation of these valuable 3a,5a-propanopiperidine derivatives and acid addition salts thereof.

Other objects will be apparent in the following description.

One important embodiment of the present invention is the acid addition salts of the compounds of the above formula (I) which are derived from pharmaceutically acceptable non-toxic acids by conventional means. Such pharmaceutically acceptable non-toxic salts include those derived from both organic and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric, embonic and like acids.

The compounds having the formula (I) have a prominent analgesic and antitussive activities. In particular, they are useful as an analgesic agent for pain after operation, chronic pain and pains caused by other diseases and generally administered orally or parenterally in an amount of from about 0.01 to 0.02 mg. as a single dose and from about 0.01 to 0.06 mg./ day for adults.

Parenteral compositions including injectable solution and suspension are most preferable, but oral composition including tablets, capsules, powders and oral suspensions may be conveniently employed. These compositions may be easily prepared from the compounds (I) or acid addition salts thereof by a conventional technique known to those skilled in the art.

According to the process of this invention, the 4B- alkoxy-4a-(3'-hydroxyphenyl) 30,5ot propanopiperidine derivatives having the formula (=1) can be prepared by reacting a 4B (or a)-hydroxy-4a (or /3)-(3'-hydroxyphenyl)- 3a,5u-propanopiperidine derivative having the formula C cm-o on,

CHa- H CH5 RiN wherein R is the same as above and R represents R; or an alkoxyalkyl group having 1-5 carbon atoms in each alkyl moiety with an alkanol having the formula ROH (111) wherein R is the same as above in the presence of an acid.

When R is an alkoxyalkyl group, it is converted to hydrogen atom in the above reaction.

The process of this invention may be carried out as usual etherification of alcohols. Namely, the reaction may be readily carried out by contacting the compound (II) with the alkanol (III) in a suitable solvent in the presence of an acid. As the solvent, an excess amount of the alkanol employed as a reactant may be preferably used. When a solvent other than the alkanol is employed, there may be preferably employed aromatic hydrocarbons, for example, benzene or toluene. As the acid used in the reaction, there may be employed a mineral acid, for example,

4a-phenyl-l-methyl-3a,5a-propanopiperidine (E) having,

the most potent analgesic activity in the known 3a,5apropanopiperidines. The analgesic activity test was carried out after 15, 30 and 60 minutes of the administration by Haffner tail pinch method [F. Haffner, Dtsch. Med. Wochschr. 55, 731 (1929)] using 5-10 male mice of approximately g. of body weight per dose and the antitussive activity test was carried out by the Mechanically Stimulating Method [K. Takagi et al., Yakugaku Zasshi (Japan) 80, 1497 (1960)] using 5 guinea pigs of approximately 300 g. of body weight per dose. The analgesic and antitussive potencies were expressed as the ED calculated by the Litchfield-Wilcoxons method [1. T. Litchfield and F. Wilcoxon, J. Pharmacol. Exp. Therap. 96, 99 (1949)]. Acute toxicities were also determined using 5 male mice of approximately 20 g. of body weight per dose. The materials were administered subcutaneously and mortalities were recorded one week later. The LD was also calculated by the Litchfield-Wilcoxons method. These sulfuric acid and phosphoric acid and an organic acid, for 20 data were shown in the following table.

ANALGESIC AND ANTITUSSIVE ACTIVITIES AND ACUTE TOXICITY OF THE PRESENT COMPOUNDS (1) ED (mg/kg.) analgesic activity Therapeutic index, LD Subcutaneous Oral ED (mg/kg.) LDw (mg/kg.) analg. EDso I antitussive acute toxicity (alter 15 min. 30 min. 60 mm. 15 mm. 30 min. 60 min. activity (s.c.) (s.c.) min.)

Compound: 1

0. 15 0. 12 0. 36 0. 105 0. 07 0. 5 0. 34 39 325. 0. 0032 0. 0032 0. 0032 0. 12 0. 12 0. 23 0. 001 200 More than 62,500. 0. 16 0. 12 0. 12 0. 74 0. 76 0. 74 0. 16 200 More than 1 Compounds-A: 4fl-methoxy-4a(3-hydroxyphenyl) 1-methyl-3a,5a-propanopiperidine; C: 4B-methoxy-4a(3' 4a(3'-methoxyphenyl)-1-phenylethyl-3a,5a-propanopipe1idine; E: 46-meth example, p-toluene-sulfonic acid. The reaction temperatures are not critical, but the reaction is usually carried out at a reflux temperature of the solvent employed. The reaction period may be varied mainly depending upon the reaction temperature and a kind of the starting material and the alkanol. The reaction is usually completed within several hours. After completion of the reaction, the desired product may be recovered from the reaction mixture by a conventional means. For instance, the reaction mixture is diluted with water, neutralized and extracted with a suitable solvent. The extract is washed with water and dried. The solvent is distilled otf to give the desired product. The product may be, if necessary, further purified by a conventional means, for example, recrystallization.

The starting materials having the formula (II) are novel and may be prepared by reacting a compound having the formula wherein R is the same as above with a phenylmagnesium bromide having the formula wherein R is the same as above. In the above reaction, there may be obtained the starting materials having the formula (II) as a mixture of stereoisomers and the mixture may be employed as starting materials in the present invention. But if necessary, it may be separated by means of chromatography. Analgesic and antitussive activities were tested about the compounds (I) and 4,6-methoxy- -1-methyl-3a,5a-propanopiperidene; B: 4Bmethoxy-4a(3rnethoxyphenyl)- -hydroxyphenyl)-1 -phenylethyl-3a,5a prop anopiperidlne; D: 4fl-methoxy oxy-4a-pheny1-1-methyl-3a,5a-propanoplperldine. From the above experimental data, it will be apparent that the present compounds (1) exhibit very potent analgesic and antitussive activities and have relatively low toxicities. The following preparations and examples are given for the purpose of illustration of this invention.

PREPARATION 1 A mixture of 4a-hydroxy-4p-(3-methoxymethoxyphenyl)-1-methyl-3a,5u-propanopiperidine and 4fi-hydroxy- 4a (3 methoxymethoxyphenyl) l methyl 3a,5apropanopiperidine (1) 5.1 g. of 50% sodium hydride mineral oil suspension is washed twice with n-hexane and suspended in 50 ml. of dimethoxymethane. To the suspension is added dropwise a solution of 17.5 g. of bromophenol in 50 ml. of dimethoxymethane with stirring and ice-cooling in nitrogen atmosphere. After the mixture is stirred for 30' minutes, 9.0 g. of chloromethyl methylether is added dropwise to the mixture and the mixture is stirred further for one hour. The reaction mixture is poured into icewater and extracted three times with benzene. The extract is dried and the solvent is distilled off to give 20 g. of 3-bromo-l-methoxymethoxybenzene as a syrup which is purified by distillation. B.P. 125-130 C/7 mm. Hg.

LR. cmf z 1599, 1578, 1478, 1155, 1000 N.M.R. (6O Mz. CDCl 6p.p.m.:

6.80-7.30 (4H, multiplet) 5.05 (2H, singlet) 3.38 (3H, singlet) Analysis-Calculated for C H O Brz C, 44.27; H, 4.18; Br. 36.81. Found: C, 44.41; H, 4.18; Br. 36.73.

(2) 3-methoxymethoxyphenylmagnesium bromide is prepared from 1.2 g. of magnesium and 10 g. of 3-bromo- 1-methxymethoxybenzene in 50 ml. of ether by a usual manner. To the Grignard solution is added dropwise a solution of 5 g. of 1-methyl-3a,5a-propano-4-piperidone in 30 ml. of dry ether over a period of 30 minutes with stirring and cooling. After 30 minutes stirring, the mix,

ture is decomposed by a careful addition of concentrated aqueous ammonia. The ether layer is collected and the aqueous layer is washed three times with ether. The combined ether layer and washings are dried and the solvent is distilled off to give 8.3 g. of a mixture of 40ahydroxy 4,8 (3' methoxymethoxyphenyl) 1 methyl- 3,5a-propanopiperidine and 4,8 hydroxy 4a (3' methoxymethoxyphenyl)-1-methyl-3u,5u propanopiperidine as a syrup.

LR. 112%, emf: 3430, 1600, 1487, 1239, 1150, 1076 1026, 1003 N.M.R. (60 ML, CDCl 6 p.p.m.:

6.80-7.32 (4H, multiplet) 5.15 (2H, singlet) 3.47 (3H, singlet) 2.22 (singlet) 1.83 (singlet) PREPARATION 2 A mixture of 4fl-hydroxy-4a-(3'-methoxyphenyl)-1-methy1-3a,5a-propanopiperidine and 4a hydroxy 4,8 (3'- methoxyphenyl) -1-methyl-3 a,5a-propanopip eridine To an ice-cold solution of 3-methoxyphenyl-magnesium bromide prepared from 6.3 g. of magnesium and 48.4 g. of 3-bromoanisol in 230 ml. of ether by a usual manner is added dropwise a solution of 31.6 g. of 1- methyl-3a,5a-propano-4-piperidone in 150 ml. of ether over a period of one hour with stirring. The mixture is stirred for one hour at room temperature and poured into ice-water. The ether layer is collected and the aqueous layer is extracted with ether four times. The combined ether layer and ether extract are extracted with a dilute sulfuric acid and the extract is made alkaline with aqueous sodium hydroxide and extracted with ether three times. The extracts are washed with water and dried. The solvent distilled off to give 52.25 g. of a mixture of 4,3 hydroxy 4a(3' methoxyphenyl) 1 methyl 3a, Six-propanopiperidine and 41x hydroxy 4,8(3 methoxyphenyl) 1 methyl 3a,5a propanopiperidine as a syrup whose thin layer chromatography reveals 2 spots.

LR. emf: 3450, 1600, 1584, 1038, 708 PREPARATION 3 4a-hydroxy-4p 3 '-hydroxyphenyl) 1- p-phenylethyl) Mia-propanopiperidine A mixture of 2.0 g. of 4a-hydroxy-4;3(3-methoxyphenyl)-1-( 3-phenylethyl)-3a,Set-propanopiperidine, 2.0 g. of sodium thioethoxide and 80 ml. of dimethylformamide is refluxed for 3 hours and then the solvent is distilled off in vacuo. The residue is dissolved in concentrated aqueous ammonium chloride and extracted with chloroform three times. The extracts are dried and the solvent is distilled off to give 2 g. of a crystalline mass. The product is recrystallized from n-hexane to give 440 mg. of the desired product as prisms melting at 9810l C.

LR. 3 1 omf 3400, 3350, 3230, 3100, 1597, 1500, 1380, 1280, 1100, 1030, 790, 742, 700.

N.M.R. (CDCl 6p.p.m.:

1.0-3.0 (18H, multiplet) 6.5-7.2 (9H, multiplet) Analysis.-Calculated for C I-I O N: C, 78.30; H,

8.07; N, 4.15. Found: C, 78.09; H, 7.97; N, 4.16.

PREPARATION 4 A mixture of 4u-hydroxy-4;8(3'-methoxyphenyl)-1-(B- phenylethyl)-3a,5u-propanopiperidine and iii-hydroxy- 4a(3' methoxyphenyl) 1 (fi phenylethyl) 30:,501- propanopiperidine (1) 1-(fi-phenylethyl)-3a,5 u-propano-4-piperidone: A mixture of 500 g. of [Si-phenylethylamine, 350 ml. of concentrated hydrochloric acid, 350 ml. of cyclohexanone, 820 ml. of 37% formalin and 5000 ml. of acetic acid is heated on a steam bath for one hour and 45 minutes and, after addition of 350 ml. of concentrated hydrochloric acid, the mixture is concentrated in vacuo. The residue is diluted with two times amount of water and washed with ether. The aqueous layer is made alkaline with sodium carbonate (anhydrous solid) and extracted with chloroform three times.

The solvent is distilled off from the extracts and the residue is dissolved with 1000 ml. of ethanol. To the ethanol solution is added gradually 300 ml. of acetic anhydride and the mixture is left to stand for 15 minutes. After addition of 350 ml. of concentrated hydrochloric acid, the mixture is concentrated in vacuo. The mixture is diluted again two times amount of water and washed with chloroform. The aqueous mixture is made alkaline with sodium carbonate (anhydrous solid) and extracted with chloroform three times. The combined extracts are dried and the solvent is distilled off. The residue is distilled to give 290 g. of a syrup, B.P. 160-180 C./ 1.5 mm. Hg which is crystallized on standing in a refrigerator.

Trituration with acetone in a Dry-Ice bath and collection of the crystals gives g. of l-(fl-phenylethyD- 3a,5a-propano-4-piperidone, M.P. 40-43 C. The analytical sample is obtained by recrystallization from n-hexane, needles, .M.P. 45-46 C.

LR. 15 1 0111.: 1735, 1712, 1e00, 1498, 1140, 743, 700

N.M.R. (CDCl;,) 6 p.p.m.:

1.0-3.3 (16H, multiplet) 7.21 (5H, singlet) Analysis-Calculated for C H ON: C, 78.93; H, 8.70; N, 5.76. Found: C, 78.65; H, 8.62; N, 5.79.

(2) A mixture of 4u-hydroxy-4B(3'-methoxyphenyl)- 1 (13 phenylethyl) 30:,50: propanopiperidine and 4,?- hydroxy 4u(3 methoxyphenyl) 1 3 phenylethyl)- 3u,5a-propanopiperidine: To a G-rignard reagent prepared from 2.0 g. of magnesium and 27 g. of 3-bromoanisol in 20 ml. of tetrahydrofuran is added dropwise a solution of 10 g. of 1-(fl-phenylethyl)-3,5a-propano-4- piperidone in 10 ml. of tetrahydrofuran while keeping at 5 C. with ice-cooling and stirring in nitrogen atmosphere. The mixture is further stirred at room temperature for 20 minutes. The mixture is diluted with saturated aqueous ammonium chloride and extracted with chloroform three times. The combined extracts are dried and evaporated to give 8.5 g. of a syrup whose thin layer chromatography indicates the prominent formation of 4a-hydroxy-4p2(3'-methoxyphenyl) 1 (fi-phenylethyl)-3a,5a propanopiperidine contaminated with a small amount of the stereoisomer. I

LR. p5 cm.- 3450, 1500, 1530, 1431, 1450, 1288, 1250, 1100, 1010, 780, 765, 740, 700.

N.M.R. (CDCI 6 p.p.m.:

1.0-3.2 (17H, multiplet) 3.77 (3H, singlet) 6.7-7.5 (9H, multiplet) 7 lization from n-hexane gives 1.3 g. of the 4p-hydroxy isomer as prisms melting at 83-4 C.

Analysis.-Ca1culated for C H O' N: C, 78.59; H, 8.32; N, 3.99. Found: C, 78.68; H, 8.48; N, 4.37.

EXAMPLE 1 4 8-methoxy-4u (3 -hydroxypheny1) -1-methyl- 3a,5a-propanopiperidine (1) In 300 ml. of absolute methanol is dissolved 10.0 g. of 4/3-hydroxy-4u(3-methoxymethoxyphenyl)-1-methyl-3a,5a-propanopiperidine and to the solution is added dropwise 30 ml. of concentrated sulfuric acid under cooling.

The solution is refluxed for 4 hours. After cooling, the reaction mixture is diluted with an equivalent amount of ice-water, made alkaline by addition of sodium carbonate and extracted with benzene. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off to give 6.9 g. of oils.

The oils are crystallized from a mixture of benzene and n-hexane to give 3.0 g. of the desired product melting at 158-160 C.

I. R. (Nujol)* v cmr z 3280, 1601, 1500, 1460, 1445, 1280, 1217, 1058 N.M.R. (60 M2. CD01 a p.p.m.: 6.65-7.40 (4H, multiplet) 5.28 (1H, singlet) 2.83 (3H, singlet) 2.23 (3H, singlet);

Analysis.-Calculated for C H O N: C, 73.58; H, 8.77; N, 5.20. Found: C, 73.53; H, 8.87; N, 5.36.

When, in the above procedure, the 4fi-methoxy-4a(3'- methoxymethoxyphenyl) piperidine compound is replaced by 4a-methoxy-4B(3'-methoxymethoxyphenyl)-l-methyl- 3a,5a-propanopiperidine or a mixture of 4fi-methoxy-4a- (3-methoxymethoxyphenyl)-l-methyl 3a,5u propanopiperidine and 4a-methoxy-4 8-(3'-methoxymethoxyphenyl)-1-methyl-3a,5a-propanopiperidine, there is obtained the same product as in the above procedure.

(2) When, in the procedure of Example 1-(1), the 4B- hydroxy-4a(3 methoxymethoxyphenyl)-1-methyl-3a,5apropanopiperidine is replaced by 4B-hydroxy-4a(3-hydroxyphenyl)-I-methyI-Sa,5a-propanopiperid-ine, there is obtained the same product as in Example 1( 1) with 40% yield.

EXAMPLE 2 4fi-methoxy-4a(3-methoxyphenyl)-1-methyl-3 :,511- propanopiperidine A mixture comprising 1.022 g. of a mixture of 4c:- hydroxy 4 3(3-methoxyphenyl-1-methyl-3mafia-propanepiperidine and a stereoisomer thereof, i.e., 4fi-hydroxy- 4oz (3' methoxyphenyl)-1-methyl-3a,5u-propanopiperidine, 40 ml. of absolute methanol and 4 ml. of concentrated sulfuric acid is refluxed for 8 hours. The reaction mixture is made alkaline by addition with aqueous ammonia and concentrated. The concentrate is diluted with water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off to give 1.116 g. of crystals. The crystals are recrystallized from n-hexane to give 0.43 g. of the desired product as needles melting at 82-83 C. The mother liquor of the recrystallization is concentrated and the concentrate is subjected to column chromatography using 40 g. of aluminaJThe eluates with a mixture *Nujol is a registered trademark for a liquid parafiin.

8 of n-hexane-chloroform (8:1 v./v.) are collected and the solvent is distilled off to give 0.22 g. of the desired product.

LR. (Nujol mull) v cmr 1602, 1579, 1070, 792

N.M.R. (CDCl 6 ppm:

2.23 (3H, singlet) 2.82 (3H, singlet) 3.85 (3H, singlet) 6.75-7.55 (4H, multiplet) Analysis-Calculated for C H O N: C, 74.14; H, 9.15; N, 5.09. Found: C, 74.73; H, 9.23; N, 5.21.

The desired product may be also obtained by using each separated stereoisomer instead of a mixture of the stereo isomers.

EXAMPLE 3 4 fi-methoxy-4a 3 -hydroxyphenyl) 1- fl-phenylethyl 3a,5a-propanopiperidine A mixture of 1.2 g. of 4a-hydroxy-4B(3'-hydroxyphenyl)-l-(flphenylethyl)-3a,5a-propanopiperidine, 40 ml. of absolute methanol and 4 ml. of concentrated sulfuric acid is refluxed for 8 hours.

The reaction mixture is poured into ice-water and the mixture is made alkaline with sodium carbonate (anhydrous solid) and extracted with chloroform. The extract is dried and the solvent is distilled off to "give 780 mg. of a syrup, which is crystallized on standing. The crystals are collected and recrystallized from n-hexane to give the desired product melting at 119 C.

EXAMPLE 4 4p-methoxy-4a(3'-methoxyphenyl)-l-(fi-phenethyD- 311,5 a-propanopiperidine A mixture of 600 mg. of 4-hydroxy-4B-(3'-methoxyphenyl) 1-(fl-phenylethyl)-3a,5a-propanopiperidine, 20 ml. of methanol and 2 ml. of concentrated sulfuric acid is refluxed for 8 hours. The reaction mixture is poured into ice-water and the mixture is made alkaline by addition of anhydrous sodium carbonate and extracted with chloroform. The extract is dried over anhydrous sodium sulfate and the solvent is distilled off to give 400 mg. of the desired product as oil.

LR. (liquid film) v cmr 1600, 1580, 1488, 1260, 1078, 1058, 700

N.M.R. (CDCl;,) 6 p.p.m.:

1.0-3.2 (16H, multiplet) 2.80 (3H, singlet) 3.80 (3H, singlet) 6.6-7.4 (9H, multiplet) Analysis.-Calculated for C H O N-H O: C, 75.16; H, 8.67; N, 3.65. Found: C, 74.74; H, 8.54; N, 3.54.

When, in the above procedure, the 4a-hydroxy-4fl(3'- methoxyphenyl)piperidine compound is replaced by the stereoisomer, i.e., 4B hydroxy-4a(3-methoxyphenyl)-1- '(fl-phenylethyl)-3a,5a-propanopiperidine or a mixture of both stereoisomers, there is obtained the same product as in the above procedure.

What is claimed is:

1. A 4,8 alkoxy-4a(3'-hydroxyphenyl)-3a,5a-propa.nopiperidine derivative having the formula C cur-of H.

2 H /CH| R1N H1 wherein R represents a straight or branched alkyl group having 1-5 carbon atoms, R represents a straight or branched alkyl group having 1-5 carbon atoms or a phenylalkyl group having 1-5 carbon atoms in the alkyl moiety and R represents hydrogen atom or a straight or branched alkyl group having 1-5 carbon atoms and pharmaceutically acceptable acid addition salts thereof.

2. 4p methoxy-4a(3'-hydroxyphenyl)-1-methyl-3u,5apropanopiperidine.

3. 4,8 methoxy-4a(3'-methoxyphenyl)-1-methy1-3a,5apropanopiperidine.

4. 4p methoxy 4a(3'-hydroxypheny1)-1-( 8-phenylethyl)-3 u,5a-propanopiperidine.

5. 4p methoxy 4a(3-methoxyphenyl)-1-(p-pheny1- ethyl)-3a,5a-propanopiperidine.

10 References Cited UNITED STATES PATENTS 3,167,562 1/1965 Iwai et a1. -1. 260- 2943 3,475,439 10/1969 Iwai et al 260-294 OTHER REFERENCES Ohki et al., Chem. Pharm. Bull. 1970, 18(10), 2050-7; Chem. Abstracts 74: 21736n (1971).

G. THOMAS TODD, Primary Examiner US. Cl. X.R. 424-26 7 

